title: Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
abstract: Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.
authors.affiliation: CHU Nantes, Service de Génétique Médicale, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.forename: Pierre
authors.initials: P
authors.lastname: Lindenbaum
authors.forename: Olivier
authors.initials: O
authors.lastname: Pichon
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bézieau
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Dominique
authors.initials: D
authors.lastname: Martin-Coignard
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D031845:Hajdu-Cheney Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D035583:Rare Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; D004247:DNA